The rate of protein-protein association plays critical roles in many fundamental biological processes, ranging from enzyme catalysis/inhibition to regulation of immunity by cytokines. Our long-term objectives are to reliably predict association rates, given just the structures of protein complexes and elucidate the mechanisms of protein-protein association. The proposed research focuses on further developments and applications of our transition-state theory for the rate of association. The foundation of the theory will be strengthened through the development of a structural model for the transition state that has a more rigorous statistical mechanical basis and explicitly accounts for the short-range nature of the interactions holding the bound complex. The theory will be applied to a broad range of protein systems to test its robustness and achieve a greater understanding of electrostatic enhancement of association rates. In particular, the study on the association of intedukin-4 (IL-4) with IL-4-binding protein will provide valuable insight for the design of IL-4 antagonists. The impact of alternative parameterizations of Poisson-Boltzmann electrostatics calculations on the predictions of the transition-state theory will be evaluated. An optimal parameterization will be selected with reference to molecular dynamics simulations. Through these further developments and example applications, the transition-state theory will become an established methodology with broad applicability to the study of protein-protein associations. The project will lay some of the fundamental groundwork towards the control of protein function by manipulating electrostatic interactions and the design of drug molecules that interfere with protein-protein interactions.